How to Manage Side Effects of Tyrosine Kinase Inhibitors in CML
Key Points
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Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia (CML) are associated with a range of toxicities affecting the gastrointestinal tract, lungs, liver, skin, blood, kidneys, and heart.
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For many of these agents, dose reductions or lower starting doses can help manage side effects without compromising efficacy.
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The OPTIC study on ponatinib showed that a response-based dose reduction strategy significantly decreased cardiovascular risk.
TKI-Associated Adverse Events
On the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, welcomed two guests, Fadi Haddad, MD, of MD Anderson Cancer Center, and Onyee Chan, MD, of Moffitt Cancer Center, to discuss the side effects associated with the six TKIs approved for CML: imatinib, dasatinib, bosutinib, nilotinib, ponatinib, and asciminib.
Of these BCR-ABL TKIs, imatinib is a first-generation agent; dasatinib, bosutinib, and nilotinib are second-generation agents; and ponatinib is a third-generation agent. The most recently approved third-generation TKI for CML, asciminib, is described as a first-in-class specifically targeting the ABL myristoyl pocket (STAMP) inhibitor because of its novel mechanism of action.
Imatinib and Class-Wide Toxicities
Imatinib is associated with many of the side effects observed across the TKI class, including fatigue, nausea, vomiting, muscle pain, cytopenias, edema, rash, headache, and diarrhea. The approved doses for imatinib are 800 mg, 600 mg, 400 mg, or 300 mg daily. Imatinib is arguably one of the best-tolerated TKIs, particularly with respect to cardiotoxicity. However, newer-generation agents are often preferred due to improved survival and response outcomes or to address mechanisms of resistance to imatinib, said Dr. Rahul Gosain.
The Side Effect Profile of Dasatinib
Fatigue, nausea, rash, cough, pyrexia, fluid retention or edema, headache, cytopenias, muscle or bone pain, and arrhythmias are commonly associated with dasatinib. Current approved doses for dasatinib are 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 140 mg, and 180 mg daily. One of the more unique side effects of dasatinib is pleural effusion, which, according to data, suggests that about 20% of patients on dasatinib will develop it over time, said Dr. Chan. Pleural effusion can be managed with diuretics or dose holds and dose adjustments, although, if it is severe enough, it may be appropriate to switch patients on dasatinib to a different TKI.
Bosutinib and Dose Adjustments When Using TKIs
Patients treated with bosutinib may experience diarrhea, nausea, transaminitis, abdominal pain, fatigue, rash, pyrexia, respiratory infection, cytopenias, headache, cough, and arrhythmias. Available dosing options for bosutinib range from 100 mg to 600 mg per day. For many of these TKIs, data suggest that dose reductions can improve tolerability without significantly compromising efficacy. Likewise, it may be effective to start patients at lower doses for each agent and then uptitrate to higher doses as long as the patient is not experiencing side effects. Ultimately, the aggressiveness of dose increases should be an individualized approach for each patient, considering comorbidities, tolerability, and disease biology, said Dr. Chan.
Navigating Nilotinib Toxicities
Nilotinib may also cause a range of side effects, including rash, pruritus, headaches, fatigue, nausea, vomiting, cardiovascular events, transaminitis, hyperbilirubinemia, cytopenias, increased lipase, hypophosphatemia, alopecia, dry skin, abdominal pain, and edema. The second-generation TKI has a capsule formulation and a reduced-dose tablet formulation. With the capsule, patients may be dosed 400 mg once daily or 300 mg or 400 mg twice daily. The tablet has approved doses of 190 mg daily, or 142 mg or 190 mg twice daily. However, nilotinib has a black box warning for QTc prolongation and sudden death.
Ponatinib: Balancing Power and Risk
The approved doses for ponatinib are 10 mg, 15 mg, 30 mg, and 45 mg daily. In addition to the class-wide side effects of TKIs, higher doses of ponatinib are associated with vascular toxicities. The label also includes a black box warning for arterial occlusive events, congestive heart failure, hepatotoxicity, and venous thromboembolisms. However, the OPTIC trial showed that reducing the dose from 45 mg daily to 15 mg daily once a patient achieved a response significantly reduced the risk of vascular events. In addition to the OPTIC dose-optimization strategy, Dr. Haddad prescribes baby aspirin and a statin alongside ponatinib in his practice for enhanced cardiovascular protection.
Asciminib Side Effects in CML Treatment
Beyond the class-related toxicities, asciminib is linked to musculoskeletal pain, upper respiratory infection, pancreatitis, arthralgias, elevated amylase or lipase, and hypertension. The approved doses for asciminib are 40 mg once daily or 20 mg twice daily, 80 mg once daily or 40 mg twice daily, 160 mg twice daily, and 200 mg twice daily. Generally, asciminib is very well tolerated compared with imatinib and the second-generation TKIs, said Dr. Chan. However, patients with baseline hypertension may require additional supportive care, she said. In chronic-phase CML, the ultimate goal is to find a dose that patients can tolerate long term without significant side effects.